COVID-19 and Nervous System: underestimated clinical and prognostic aspects

Research Article | DOI: https://doi.org/10.31579/2690-8794/023

COVID-19 and Nervous System: underestimated clinical and prognostic aspects

  • Alyne Barreto Mesquita de Goés 1
  • Bruno Barreira Cardoso 1
  • Francisco de Assis Fernandes Tavares 1
  • Rebecca Renata Lapenda do Monte 1
  • Renata Carneiro Melo 1
  • Irami Araújo-Neto 1
  • Renato Serquiz Elias Pinheiro 2
  • Amália Cinthia Meneses Rêgo 3
  • Irami Araújo-Filho 4*

1 Undergraduate Student of Medicine at UnP - Potiguar University - Laureate International Universities – Natal/Brazil; 
2 Neurologist and Professor at Potiguar University / UnP - Laureate International Universities – Natal/Brazil; 
3 Postgraduate Program in Biotechnology at Potiguar University / UnP - Laureate International Universities. Teaching and Research Manager - School of Health - League against Cancer Natal - RN / Brazil. Ph.D. in Health Science; 
4 Postgraduate Program in Biotechnology at Potiguar University/ UnP - Laureate International Universities; Full Professor Department of Surgery, Federal University of Rio Grande do Norte. Full Professor, Department of Surgery, Potiguar University. Ph.D in Health Science/ Natal-RN, Brazil

*Corresponding Author: Irami Araújo-Filho, Postgraduate Program in Biotechnology at Potiguar University/ UnP-Laureate International Universities; Full Professor Department of Surgery, Federal University of Rio Grande do Norte. Full Professor, Department of Surgery, Potiguar Uni

Citation: Rebecca Renata Lapenda do Monte, Francisco de Assis Fernandes Tavares, Bruno Barreira Cardoso, Alyne Barreto Mesquita de Goes, Thais Cristina Loyola da Silva, Brenda de Oliveira Silva, Yara Saiane Marim Araujo, Amália Cinhtia Meneses Rêgo, Irami Araújo-Filho. Clinical Medical Reviews and Reports. 2(4); DOI: 10.31579/2690-8794/023

Copyright: © 2020, Irami Araújo-Neto. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Received: 26 May 2020 | Accepted: 19 June 2020 | Published: 26 June 2020

Keywords: covid-19 pandemic; sars-cov-2 infection; coronavirus; central nervous system viral diseases; peripheral nervous system diseases; injury

Abstract

The coronavirus pandemic transformed the world abruptly due to the speed of transmission and high morbidity and mortality. Many deaths have been quantified, and the scientific community intensifies the search for molecular targets, protein sequences and polymorphisms on SARS-CoV-2, to improve the clinical evolution and survival of patients. Initially, COVID-19 was described with respiratory changes, flu, and fever. With the spread of the disease, clinical manifestations were observed in other organ systems, still unknown. In this sense, the present study describes the main neurological changes and laboratory findings. The literature review was identified in the central databases: Scielo, Google Scholar, PubMed / MedLine, Embase, and Cochrane Database. Twenty-five articles related to the theme were chosen, including reviews, case series, cohort, and retrospective studies. Neurological manifestations were predominantly anosmia/hyposmia, dysgeusia, ataxia, and seizures. According to the latest published studies, attention must be paid to isolated initial neurological events.

Introduction

The new coronavirus appeared in the city of Wuhan in China, and, due to its high infectivity, it spread quickly to the whole world. SARS-CoV-2 was responsible for the critical state of the pandemic that we are experiencing today. The clinical syndrome caused by SARS-CoV-2 was called COVID-19 [1, 2].

The signs and symptoms are clinically indistinguishable from those of the flu. Studies have described fever (43.8% on admission and 88.7% during hospitalization), cough (67.8%), fatigue (50%), headache (8%), and diarrhea (5%). However, the disease affects other organ systems and evolves with varied clinical manifestations [1,3].

In addition to changes in the respiratory system, patients with COVID-19 may have neurological syndromes, loss of involuntary breathing process, impairment of the brain stem, ataxia, loss of smell, seizures, among others. These manifestations are usually alarming and signal a worse prognosis [1].

Neurological changes seen in patients with severe infection include acute cerebrovascular events, impaired consciousness, areflexia, paraesthesia, and muscle injury [3].

As the emergence of the pandemic, the recognition of neurological clinical findings is in its early stages. Thus, little is known about the syndromic complexity of COVID-19. Still, it is believed that the neurological disorders of the disease are similar to the data previously described by the infection of SARS-CoV-1, a virus of the same family [3].

No vaccine or antiviral treatment specific to COVID-19 has yet been shown to be effective. For this reason, several preventive measures have been suggested to minimize the damage caused by the disease, personal protection, social distance, adequate hygiene measures, and isolation of confirmed cases. Identifying and treating patients as quickly as possible, especially patients considered to be at high risk, is crucial to reducing the mortality rate [4].

Mortality is higher among elderly patients and patients with comorbidities, including diabetes, cardiac, respiratory disorders, and immunosuppressed. [4]

This article describes the main neurological signs and symptoms reported in the literature and correlates these findings with etiopathogenic mechanisms, laboratory tests, and prognostic factors.

Methods

The present study was carried out based on searches in PubMed / Medline, Scopus, Scielo, Embase, and Web of Science databases in addition to the Google Scholar search, considered as a source of gray literature, as it does not contain peer-reviewed articles. Studies related to neurological manifestations of the coronavirus were selected, being chosen through the combination of the following keywords: neurological signs and COVID-19. All relevant studies published between 2019 and 2020 were included in the cohort, systematic review, case-control, cross-sectional, case series studies, and randomized clinical trials. The filters chosen were studies carried out in humans, complete articles, and recently published, totaling twenty-five articles. analysis, review, and selection of the articles were made by peers blindly, from reading the title and summary of the study, with a third reviewer in case of disagreement between the other two reviewers.

Results and Discussion

The coronavirus family comprises viruses that cause diseases with different clinical manifestations, which can vary from a common cold to severe clinical conditions. SARS-CoV-2 is the new coronavirus, first detected in China and spreading globally [1].

The average age of onset is 35-55 years of age, with a lower prevalence in children. Most patients are male, and the main risk groups are immunosuppressed patients with renal and hepatic dysfunction. Transmission can occur through droplets, aerosols, and contaminated surfaces, when in contact with the mouth, nose, or eyes of susceptible individuals. There is an increase in the number of cases transmitted through the feces of infected patients [5].

To date, there is no specific consolidated treatment regime for COVID-19, which is why the importance of symptomatic management is essential. Thus, atypical symptoms must be taken into account during anamnesis and physical examination of patients, since the evolution of the disease, in these cases, can be more severe. Patients may experience respiratory, digestive, liver problems, and disorders of the nervous system [6-8].

Nath A. el al. subdivided these into manifestations that occur at the time of infection and post-infection events. Encephalopathy, hypoventilation, viral meningitis, anosmia, ageusia, encephalitis, stroke, myositis, and acute hemorrhagic encephalopathy are parainfectious symptoms. Transverse myelitis, Guillan-Barré syndrome, sensory neuropathy, brainstem encephalitis, and acute transverse encephalomyelitis, usually occur after COVID-19 infection [7-9].

Health system

The measurement of neurological disorders based on signs and symptoms, as well as the patients' prognosis, can be assessed through the protocol developed by the World Health Organization (WHO) in February 2020. In this, respiratory findings are addressed; however there is a specific column to detect the neurological aspects involved [8,9].

It is important to note that these clinical presentations are being released to the world in real-time by the number of "First Few X cases (FFX) and their close contacts" by WHO. Several cases have been described, with nonspecific manifestations such as loss of smell, headache, seizures, and hemiparesis [8,10].

Pathophysiology

SARS-COV and MERS-COV have neuro-invasive properties, which can be detected in the human brain [9]. The pathophysiology of the lesions has not yet been clarified concerning COVID-19; however, it is believed that it occurs via hematogenous, reaching the Central Nervous System (CNS) or by retrograde neuronal dissemination, due to the proximity of the cribriform plate of the ethmoidal bone. Depending on this theory, there is a report of hyposmia in several patients [11].

Also, it is known that the primary target cells for SARS-CoV-2 are the epithelial cells of the respiratory and gastrointestinal tract, which contain the angiotensin-converting enzyme 2 (ACE2), which is also present in the CNS and skeletal musculature. This enzyme is usually used by the virus to invade cells, for which it presents tropism [2, 10-12].

Inhalation of SARS-CoV-110 or MERS-CoV-11 resulted in the rapid invasion of viral particles in the brain, possibly through the olfactory bulb via the trans-synaptic route. Several viruses penetrate this pathway into the peripheral nerves and spread through the CNS through synaptic contacts [5-7]. 

The brain stem, where the neuronal respiratory bulb is located in the medulla, has been severely infected by both types of viruses, which can contribute to respiratory failure. On the other hand, it was observed that when nasal viral loads were inhaled in low concentrations, only the CNS was colonized, with the absence of viruses in other tissues, including the lungs, corroborating the existence of the neurotropism of the coronavirus strains by the CNS [2-4].

Due to retrograde neuronal dissemination, Li et al. advocate that the use of protective masks and antiviral drugs at the beginning of the disease should be encouraged to prevent CNS involvement [11-13]

A severe complication of COVID-19 infection is Acute Disseminated Encephalomyelitis, a syndrome described in patients with HCoV-OC43, which occurs approximately two weeks after infection. This syndrome is also expected to happen in SARS-CoV-2 [7,14].

The presence of the virus in the brain stem can affect chemosensory neural cells associated with respiratory and cardiovascular regulation, as well as neurons in the bulbar respiratory center (brain stem), affecting ventilatory lung function. An additional factor to the hypothesis that the nasal route may contribute to the entry of the virus in the brain is provided by clinical observations of anosmia, a new and profound mark in individuals infected with SARS-CoV-2 [1-3].

The infection by SARS-CoV-2 in the CNS triggers an intense systemic inflammatory reaction with a massive release of cytokines, chemokines, and other inflammatory mediators, with subsequent breakdown of the blood-brain barrier and amplifies the viral neuro-infection process [15-17].

The higher the plasma concentration of cytokines, the greater the need for intensive care. Pre-clinical and clinical studies have shown that systemic inflammation promotes neuroinflammation that severely affects cerebral homeostasis and causes the death of central and peripheral neurons [2, 11, 12].

Neurological symptoms

According to Baig et al., COVID-19 and SARS-CoV-1 have similar taxonomy. SARS-CoV-1 promotes neurological deficits and has already been isolated in brain tissue. In this sense, the coronavirus is expected to follow the same trend [3].

Neurological manifestations are classified into two categories: those that affect the Central Nervous System (CNS) and those that affect the Peripheral Nervous System (PNS). Clinical findings related to the CNS include vertigo, headache, impaired consciousness, acute vascular brain disease, ataxia, and epilepsy. SNP involvement causes hyposmia, neuralgia, and hypogeusia [13,18].

As for SARS-CoV-2, there is no exact description of what signs and symptoms to investigate or which neurological tests are indispensable in the physical examination of patients, as some, such as hyposmia and hypogeusia, are usually so mild that they are not present in most of the cases [19-20]. 

However, if there is a report or the presence of deficits, it is essential to perform laboratory tests, such as urea, creatinine, electrolytes, and blood gas analysis (PO2 and PCO2), as the results can corroborate for a possible primary or secondary involvement of the CNS. [3, 14]

The American Academy of Otorhinolaryngological Surgery (AACO) recently released that patients with COVID-19 may experience dysgeusia or hyposmia. These are the primary evidence that should be researched. It is believed that the virus causes inflammation in the olfactory nerves, instead of damaging the structure of the receptors, as the olfactory system can always fight pathogens and their dysfunctions are temporary. Generally, these same patients experience loss of taste [3, 15].

Based on the cases reported by AACO, it is recommended to investigate COVID-19 if the patient says anosmia, hyposmia, or dysgeusia in the absence of other respiratory diseases, such as acute or chronic rhinosinusitis and allergic rhinitis. The “COVID-19 Anosmia Report Tool for Clinicians” was made available by AAO-HNS to facilitate this diagnosis [15,16].

Anosmia is mostly transient, but it has been seen that in some patients, it has become permanent. As the lesion occurs due to invasion of the olfactory pathways, the monitoring of these patients should be encouraged for an extended period, to ensure that other neuroinflammatory diseases can be ruled out [7,21].

The meningitis clinic is controversial, as some studies report that neuronal deaths with inflammation of the brain substance have not been detected. However, Wu et al. report a case from Hospital Beijing Ditan, identified employing the genomic sequencing technique of the presence of SARS-CoV-2 in the cerebrospinal fluid. The patient was diagnosed with viral encephalitis, and SARS-CoV-2 attacked the central nervous system. The virus has mechanisms of direct invasion to the nervous system, in addition to the immune response to the pathogen [3, 9, 10] 

It is inquired about the acute toxic viral encephalitis syndrome, from manifestations such as headache, consciousness disorder, and cerebral edema seen in autopsies. Thus, it is necessary to analyze the CSF of patients with these manifestations in search of the viral genome and inflammatory cells. [4-6,10]

In Japan and China, two cases of meningoencephalitis and encephalitis have been reported, respectively. Both had generalized seizures and acute respiratory distress syndrome. One of them presented lesions in the temporal lobe with adjacent ventriculitis and injuries in the paranasal sinuses [16-18]. 

The exciting thing was that the virus could be isolated in the CSF, but it was not detected in the nasal swabs. However, it is essential to emphasize that CSF should only be collected in cases where neuroimaging tests do not clarify the patient's symptoms or in cases of infectious or autoimmune processes [7,19].

In a series of cases with 214 patients, neurological symptoms were observed in 36.4%, being more common in patients with severe respiratory status (45.5%), with reports of acute cerebrovascular events, impaired consciousness, and muscle injury [1,3].

In patients described with severe infection, 5.7

Conclusion

In conclusion, SARS-CoV-2 can affect the central or peripheral nervous system. Patients affected by COVID-19 associated with neurological clinical manifestations evolve with greater severity. Thus, health professionals must know the atypical signs of the disease, as patients who do not have accompanying respiratory symptoms are considered a critical hidden source of the virus's spread.

Therefore, immediate diagnostic suspicion and early identification of these patients is necessary to contain the viral transmission, avoid clinical deterioration, and reduce mortality rates. The primary purpose of this review was to assist professionals in investigating neurological changes since the onset of the condition, avoiding an increase in the transmissibility of the disease and worse clinical outcomes.

Highlights

  • In a pandemic situation, symptoms such as hyposmia or hypogeusia should alert COVID-19, even when respiratory conditions are not described.
  • Syncope, headache, seizures, hemiplegia, and decreased level of consciousness have been reported in positive cases for SARS-CoV-2.
  • Lymphopenia, thrombocytopenia, and urea elevation correlate with the presence of symptoms in the CNS.

Acknowledgments

The authors thank the Ph.D. in Health Sciences and Teaching and Research Manager at League Against Cancer, Profa. Dra. Amália Rêgo, for her contribution and relevance to the scientific discussion and supervision of this review, acting as an expert consultant on the bibliographic survey, analysis, and scientific advice. We also thank all the study components for their dedication and effort to build a scientifically validated quality study.

Disclosure of conflict of interest

There are no conflicts of interest to declare by any of the authors of this study.

References

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